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Subjects

Abstract

Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1∆/−) show numerous accelerated ageing features that limit their lifespan to 4-6 months1,2,3,4. They also exhibit a ‘survival response’, which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction)1,5. Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg−/− (also known as Ercc5−/−) mice, a model of Cockayne syndrome6, responded similarly. The dietary restriction response in Ercc1∆/− mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1∆/− mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1∆/− mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.

Acknowledgements

We thank P. de With, J. Rigters, E. Haasdijk, S. Gabriels, E. J. M. Stynenbosch, N. van Vliet, Y. van Loon, J. Baan and the animal caretakers for general assistance with mouse experiments. We thank A. H. J. Danser and J. P. van Leeuwen for support. We acknowledge financial support from the National Institute of Health (NIH)/National Institute of Ageing (NIA) (1PO1 AG-17242-02), the National Institute for Public Health and the Environment and the Ministry of Health, Welfare and Sport of The Netherlands (S/340005), European Research Council Advanced Grant DamAge and Proof of Concept Grant Dementia to J.H.J.H., the European commission FP7 Markage (FP7-Health-2008-200880), DNA Repair (LSHG-CT-2005-512113), EU ITN Address (GA-316390), the KWO Dutch Cancer Society (5030), the Dutch CAA Foundation and the Royal Academy of Arts and Sciences of the Netherlands (academia professorship to J.H.J.H.). The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number HEALTH-F2-2010-259893. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Videos

AL-fed Ercc1δ/− mouse (shown on the right), at 16 weeks of age, shows abnormal gait, trembling and balance problems. These age-related neurological symptoms are absent in the littermate DR Ercc1δ/− mouse (left) at 16 weeks but eventually may develop after 35 weeks of age (see Figure 2a-c). Video contains audio comments. (reference to website with access to the video: http://cluster15.erasmusmc.nl/drvideos/index.html).

Wildtype AL and DR and Ercc1δ/− AL and DR mice, form right to left respectively, were tested for locomotor performance on an accelerating rotarod. The average time of four animals per group is shown in Figure 2d. Video contains audio comments. (reference to website with access to the video: http://cluster15.erasmusmc.nl/drvideos/index.html).

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Editorial Summary

Mouse models of dietary restriction

Dietary restriction is well established as an intervention that can extend lifespan and delay many signs of ageing in numerous species, but the underlying mechanisms remain unresolved. Jan Hoeijmakers and colleagues have examined the effects of dietary restriction in two mouse models with defective DNA repair that develop signs resembling those seen in human progeroid syndromes, which cause children to age at an accelerated rate. Strikingly, a dietary restriction of 30% substantially increased lifespan in both models and mice on the restricted diets maintained more neurons and better motor function than controls. In particular, the authors suggest DNA-repair-deficient Ercc1Δ/− mice as an effective model for the study of the effects of dietary restriction and for testing therapeutic interventions.